Letermovir vs Valganciclovir for Prophylaxis of Cytomegalovirus in High-Risk Kidney Transplant Recipients: A Randomized Clinical Trial.

Importance: Valganciclovir for 200 days is standard care for cytomegalovirus (CMV) prophylaxis in high-risk CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor, but its use is limited by myelosuppression. Objective: To compare the efficacy and safety of letermovir with valganciclovir for prevention of CMV disease in CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor. Design, Setting, and Participants: Randomized, double-masked, double-dummy, noninferiority, phase 3 trial in adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor at 94 participating sites between May 2018 and April 2021 (final follow-up in April 2022). Interventions: Participants were randomized in a 1:1 ratio (stratified by receipt of lymphocyte-depleting induction immunosuppression) to receive letermovir, 480 mg, orally daily (with acyclovir) or valganciclovir, 900 mg, orally daily (adjusted for kidney function) for up to 200 days after transplant, with matching placebos. Main Outcomes and Measures: The primary outcome was CMV disease, confirmed by an independent masked adjudication committee, through posttransplant week 52 (prespecified noninferiority margin, 10%). CMV disease through week 28 and time to onset of CMV disease through week 52 were secondary outcomes. Exploratory outcomes included quantifiable CMV DNAemia and resistance. The rate of leukopenia or neutropenia through week 28 was a prespecified safety outcome. Results: Among 601 participants randomized, 589 received at least 1 dose of the study drug (mean age, 49.6 years; 422 [71.6%] men). Letermovir (n = 289) was noninferior to valganciclovir (n = 297) for prevention of CMV disease through week 52 (10.4% vs 11.8% of participants with committee-confirmed CMV disease; stratum-adjusted difference -1.4% [95% CI, -6.5% to 3.8%]). No participants who received letermovir vs 5 participants (1.7%) who received valganciclovir developed CMV disease through week 28. Time to onset of CMV disease was comparable between the groups (hazard ratio, 0.90 [95% CI, 0.56-1.47]). Quantifiable CMV DNAemia was detected in 2.1% of participants in the letermovir group vs 8.8% in the valganciclovir group by week 28. Of participants evaluated for suspected CMV disease or CMV DNAemia, none (0/52) who received letermovir and 12.1% (8/66) who received valganciclovir had resistance-associated substitutions. The rate of leukopenia or neutropenia through week 28 was lower with letermovir vs valganciclovir (26% vs 64%; difference, -37.9% [95% CI, -45.1% to -30.3%]; P < .001). Fewer participants in the letermovir group than the valganciclovir group discontinued prophylaxis due to adverse events (4.1% vs 13.5%) or drug-related adverse events (2.7% vs 8.8%). Conclusion and Relevance: Among adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor, letermovir was noninferior to valganciclovir for prophylaxis of CMV disease over 52 weeks, with lower rates of leukopenia or neutropenia, supporting its use for this indication. Trial Registration: ClinicalTrials.gov Identifier: NCT03443869; EudraCT: 2017-001055-30.

Immune checkpoint inhibitors in kidney transplant recipients: a multicentre, single-arm, phase 1 study.

BACKGROUND: Most kidney transplant recipients with cancer stop or reduce immunosuppressive therapy before starting treatment with an immune checkpoint inhibitor, and approximately 40% of such patients will develop allograft rejection. Isolated immunosuppression reduction might be associated with organ rejection. Whether immunosuppression manipulation, immune checkpoint inhibition, or both, induce organ rejection is difficult to ascertain. The aim of this study was to examine the risk of allograft rejection with immune checkpoint inhibitor exposure when baseline immunosuppression was left unchanged. METHODS: We conducted a multicentre, single-arm, phase 1 study in three hospitals in Australia. Kidney transplant recipients aged 18 years or older with incurable, locally advanced cancer or defined metastatic solid tumours were eligible if they had a creatinine concentration of less than 180 mmol/L, no or low concentrations of donor-specific HLA antibodies, and an Eastern Cooperative Oncology Group status of 0-2. Patients received standard doses of nivolumab (3 mg/kg intravenously every 14 days for five cycles, then 480 mg every 28 days for up to 2 years). The primary endpoint was the proportion of patients with irretrievable allograft rejection and no evidence of tumour response. Primary outcome analyses and safety analyses were done in the modified intention-to-treat population. This trial is registered with the Australian and New Zealand Clinical Trials Register, ANZCTR12617000741381, and is completed. FINDINGS: Between May 31, 2017, and Aug 6, 2021, 22 kidney transplant recipients with various solid tumours were screened and enrolled, four of whom chose not to proceed in the study and one of whom had unexpected disease progression. 17 patients (six [35%] women and 11 [65%] men; median age 67 years [IQR 59-71]) were allocated treatment with nivolumab and were included in the analyses. The trial was then stopped due to ongoing difficulties with running clinical trials during COVID-19 health restrictions. Patients were treated with a median of three infusions (IQR 2-10) and median follow-up was 28 months (IQR 16-34). No patients had irretrievable allograft rejection without evidence of tumour response. There were no treatment-related deaths or treatment-related serious adverse events. The most common grade 3 or grade 4 adverse events were decreased lymphocyte count in four (24%) patients, fever or infection in four (24%) patients, decreased haemoglobin in three (18%) patients, and increased creatinine in three (18%) patients. INTERPRETATION: Maintaining baseline immunosuppression before treatment with an immune checkpoint inhibitor in kidney transplant recipients might not affect expected efficacy and might reduce the risk of allograft rejection mediated by immune checkpoint inhibitors. FUNDING: Bristol Myers Squibb.

A novel non-invasive index of oxygenation and prediction of outcomes for patients on high-flow nasal cannula: a pilot study.

Predicting success of a therapy in acute respiratory failure is clinically important. The FOx index (high-flow rate × FiO2 )/SpO2 was retrospectively applied to 70 patients who required high-flow nasal prongs for hypoxaemic and hypercapnic respiratory failure. The FOx index could predict between success and failure of high-flow nasal prongs at 6 hours, using non-invasive markers. This adds to the clinician's toolbox in managing respiratory failure and represents important proof of concept for a prospective study.

Effects of Arteriovenous Fistula Ligation on Cardiac Structure and Function in Kidney Transplant Recipients.

BACKGROUND: Cardiovascular morbidity and mortality remain high in recipients of a kidney transplant. The persistence of a patent arteriovenous fistula (AVF) after transplantation may contribute to ongoing maladaptive cardiovascular remodeling. The ability to reverse this maladaptive remodeling by ligation of this AVF is unknown. We conducted the first randomized controlled trial to evaluate the effect of AVF ligation on cardiac structure and function in stable kidney transplant recipients. METHODS: In this randomized controlled trial, kidney transplant recipients (>12 months after transplantation with stable graft function) were randomized to AVF ligation or no intervention. All participants underwent cardiac magnetic resonance imaging at baseline and at 6 months. The primary outcome was the change in left ventricular (LV) mass. Secondary outcomes included changes in LV volumes, left and right atrial areas, LV ejection fraction, NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, cardiac output/index, brachial flows (ipsilateral to AVF), and pulmonary artery velocity. RESULTS: A total of 93 patients were screened, of whom 64 met the inclusion criteria and were randomized to the AVF ligation (n=33) or control (n=31) group. Fifty-four participants completed the study: 27 in the AVF ligation group and 27 in the control group. On the second cardiac magnetic resonance scan, a mean decrease of 22.1 g (95% CI, 15.0-29.1) was observed in LV mass in the AVF ligation group compared with a small increase of 1.2 g (95% CI, -4.8 to 7.2) in the control group ( P<0.001). Significant decreases in LV end-diastolic volumes, LV end-systolic volumes, cardiac output, cardiac index, atrial volumes, and NT-proBNP were also seen in the AVF closure group ( P<0.01). No significant changes were observed in LV ejection fraction ( P=0.93) and pulmonary artery velocity ( P=0.07). No significant complications were noted after AVF ligation. No changes in estimated glomerular filtration rate or systolic and diastolic blood pressures were observed between cardiac magnetic resonance scans. CONCLUSIONS: Elective ligation of patent AVF in adults with stable kidney transplant function resulted in clinically significant reduction of LV myocardial mass. CLINICAL TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry URL: https://www.anzctr.org.au . Unique Identifier: ACTRN12613001302741.

Mycophenolic acid concentrations in peripheral blood mononuclear cells are associated with the incidence of rejection in renal transplant recipients.

AIMS: Although therapeutic drug monitoring of plasma mycophenolic acid (MPA) concentrations has been recommended to individualize dosage in transplant recipients, little is known regarding lymphocyte concentrations of MPA, where MPA inhibits inosine monophosphate dehydrogenase (IMPDH). This study investigated the utility of measuring predose MPA concentrations in peripheral blood mononuclear cells (C0C ) and predose IMPDH activity, as predictors of graft rejection in renal transplant recipients. METHODS: Forty-eight patients commencing mycophenolate mofetil (1 g twice daily) in combination with tacrolimus and prednisolone were recruited. Blood was collected for determination of trough total (C0P ) and unbound (C0u ) plasma MPA concentrations. Peripheral blood mononuclear cells were isolated for determination of C0C and IMPDH activity. The incidence of rejection within 2 days of sample collection was determined histologically and classified according to the Banff 2007 criteria. RESULTS: There was no association between MPA C0C and C0P (rs  = 0.28, P = 0.06), however, MPA C0C were weakly correlated with MPA C0u (rs  = 0.42, P = 0.013). Multivariate analysis indicated that MPA C0C was the only covariate independently associated with rejection (FDR-adjusted P = 0.033). The receiver operating characteristic area under the curve (AUC) for the prediction of severe rejection using MPA C0C was 0.75 (P = 0.013), with 73% sensitivity and specificity at a C0C threshold of 0.5 ng 10-7 cells. However, predose IMPDH activity was not a predictor of rejection (P > 0.15). CONCLUSIONS: MPA C0C measurement within the early post-transplant period may be useful to facilitate early titration of MPA dosing to significantly reduce rejection.

Carvedilol and Cardiac Biomarkers in Dialysis Patients: Secondary Analysis of a Randomized Controlled Trial.

BACKGROUND/AIMS: Cardiac biomarkers are associated with cardiac abnormalities and adverse outcomes in dialysis patients. Our aim was to report the effect of the beta-blocker carvedilol on cardiac biomarkers in adult dialysis patients. METHODS: The Beta-Blocker to Lower Cardiovascular Dialysis Events Feasibility Study was a randomized controlled trial comparing carvedilol to placebo. Serum and plasma were collected before the run-in, then 6 and 12 months post-randomization to measure B-type Natriuretic Peptide (BNP), N-terminal BNP (NT-ProBNP), high-sensitivity cardiac troponins I (hs-TnI) and T (hs-TnT), and galectin-3. Left ventricular global longitudinal strain (GLS) was measured by echocardiography at baseline. RESULTS: Seventy-two participants were recruited of whom 49 completed the run-in and were randomized to carvedilol (n=26) or placebo (n=23). Baseline echocardiography demonstrated median (inter-quartile range) GLS of -14.27% (-16.63 to -11.93). NTproBNP and hs-TnT correlated with GLS (Spearman's rho=0.34 [p=0.018] and rho=0.28 [p=0.049], respectively). Median change scores from baseline to 12 months did not differ significantly between participants with complete biomarker data randomized to carvedilol (n=15) or placebo (n=16) for any biomarkers. CONCLUSIONS: NT-proBNP and hs-TnT were associated with GLS. However, changes in levels of the biomarkers from baseline to 12 months were not different between groups randomized to carvedilol and placebo.

Interleukin-17A-Induced Human Mesenchymal Stem Cells Are Superior Modulators of Immunological Function.

Interferon-γ (IFN-γ)-preactivated mesenchymal stem cells (MSC-γ) are highly immunosuppressive but immunogenic in vivo due to their inherent expression of major histocompatibility (MHC) molecules. Here, we present an improved approach where we modified human bone marrow-derived MSC with interleukin-17A (MSC-17) to enhance T cell immunosuppression but not their immunogenicity. MSC-17, unlike MSC-γ, showed no induction or upregulation of MHC class I, MHC class II, and T cell costimulatory molecule CD40, but maintained normal MSC morphology and phenotypic marker expression. When cocultured with phytohemagglutinin (PHA)-activated human T cells, MSCs-17 were potent suppressors of T cell proliferation. Furthermore, MSC-17 inhibited surface CD25 expression and suppressed the elaboration of Th1 cytokines, IFN-γ, tumor necrosis factor-α (TNF-α), and IL-2 when compared with untreated MSCs (UT-MSCs). T cell suppression by MSC-17 correlated with increased IL-6 but not with indoleamine 2,3-dioxygenase 1, cyclooxygenase 1, and transforming growth factor ß-1. MSC-17 but not MSC-γ consistently induced CD4(+) CD25(high) CD127(low) FoxP3(+) regulatory T cells (iTregs) from PHA-activated CD4(+) CD25(-) T cells. MSC-induced iTregs expressed CD39, CD73, CD69, OX40, cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), and glucocorticoid-induced TNFR-related protein (GITR). These suppressive MSCs-17 can engender Tregs to potently suppress T cell activation with minimal immunogenicity and thus represent a superior T cell immunomodulator for clinical application.

Peripheral natural killer cell and allo-stimulated T-cell function in kidney transplant recipients associate with cancer risk and immunosuppression-related complications.

Reducing immunosuppression has been proposed as a means of preventing cancer in kidney transplant recipients but this can precipitate graft rejection. Here we tested whether anti-tumor natural killer (NK) cell and allo-responsive T-cell function in kidney transplant recipients may predict cancer risk and define risk of rejection. NK cell function was measured by the release of lactate dehydrogenase and T-cell allo-response by interferon-γ quantification using a panel of reactive T-cell enzyme-linked immunospot (ELISPOT) in 56 kidney transplant recipients with current or past cancer and 26 kidney transplant recipients without cancer. NK function was significantly impaired and the allo-response was significantly lower in kidney transplant recipients with cancer. With prospective follow-up, kidney transplant recipients with poor NK cell function had a hazard ratio of 2.1 (95% confidence interval 0.97-5.00) for the combined end point of metastatic cancer, cancer-related death, or septic death. Kidney transplant recipients with low interferon-γ release were also more likely to reach this combined end point. Thus, posttransplant monitoring of allo-immunity and NK cell function is useful for assessing the risk of over immunosuppression for the development of malignancy and/or death from cancer or sepsis.

Reductions in immunosuppression after haematological or solid organ cancer diagnosis in kidney transplant recipients.

Few data exist on how immunosuppression is altered in kidney transplant recipients (KTR) following a diagnosis of cancer. This study investigated how immunosuppression was altered in KTR after cancer diagnosis and its effect on patient and graft survival. All KTR diagnosed with cancer at our centre from 1990 to 2012 were assessed. Drug regime and serum creatinine levels were recorded 1 year before, at time of, and 1 year after cancer diagnosis. Of 87 KTR who developed cancer (7.3% of transplanted population, n = 1189), 30 developed haematological malignancies and 57 developed solid organ cancers (SOC). In total, 38% of KTR presented with nodal or metastatic disease and 23 of 87 (26%) KTR died within 6 months of cancer diagnosis. Fifty-five KTR had records of pre- and postcancer diagnosis drug regimes. Thirty-six KTR had a (>50%) dose reduction or cessation of 1 or more immunosuppressive agents, and 19 no reduction in immunosuppression. In total, 2 of 36 (6%) of KTR who underwent a dose reduction suffered acute rejection that was reversed with methylprednisolone. Dose reduction/cessation of immunosuppression did not impair graft function, but also did not affect cancer free survival. Further larger prospective studies are needed to determine whether dose reduction alters relapse free cancer survival in KTR.

C4d-negative antibody-mediated rejection with high anti-angiotensin II type I receptor antibodies in absence of donor-specific antibodies.

AIMS: Acute antibody-mediated rejection can occur in absence of circulating donor-specific antibodies. Agonistic antibodies targeting the anti-angiotensin II type 1 receptor (anti-AT1 R) are emerging as important non-human leucocyte antigen (HLA) antibodies. Elevated levels of anti-angiotensin II receptor antibodies were first observed in kidney transplant recipients with malignant hypertension and allograft rejection. They have now been studied in three separate kidney transplant populations and associate to frequency of rejection, severity of rejection and graft failure. METHODS: We report 11 cases of biopsy-proven, Complement 4 fragment d (C4d)-negative, acute rejection occurring without circulating donor-specific anti-HLA antibodies. In eight cases, anti-angiotensin receptor antibodies were retrospectively examined. The remaining three subjects were identified from our centre's newly instituted routine anti-angiotensin receptor antibody screening. RESULTS: All subjects fulfilled Banff 2013 criteria for antibody-mediated rejection and all responded to anti-rejection therapy, which included plasma exchange and angiotensin receptor blocker therapy. CONCLUSIONS: These cases support the routine assessment of anti-AT1 R antibodies in kidney transplant recipients to identify subjects at risk. Further studies will need to determine optimal assessment protocol and the effectiveness of pre-emptive treatment with angiotensin receptor blockers.

Angiotensin II type 1 receptor antibody precipitating acute vascular rejection in kidney transplantation.

Atypical non HLA antibodies are increasingly recognised as causes of immunological injury in allotransplantation. In this report we describe a non HLA sensitized male renal allograft recipient who developed acute vascular rejection on a "for cause" biopsy (Banff v2, g2, ptc 3) at day 4 post first renal allograft in the presence of elevated angiotensin II type 1 receptor antibodies (AT1R-Ab level 14.1). The acute rejection was treated with pulse corticosteroid therapy, anti-thymocyte globulin (ATG × 6), plasma exchange (1.5 plasma volume replacement x6) and oral candesartan. Serum creatinine improved and follow up biopsy confirmed resolution of rejection following treatment. AT1R-Ab should be considered when rejection is diagnosed in the absence of HLA antibodies.

The immune phenotype may relate to cancer development in kidney transplant recipients.

High regulatory T-cell (Treg) numbers predict recurrent cutaneous squamous cell carcinoma in kidney transplant recipients, and the Treg immune phenotype may identify kidney transplant recipients at risk of developing squamous cell carcinoma and/or solid-organ cancer. To investigate this, a total of 116 kidney transplant recipients, of whom 65 had current or past cancer, were immune-phenotyped and followed up prospectively for a median of 15 months. Higher Treg (CD3+CD4+FOXP3+CD25(Hi)CD127(Lo)) proportion and numbers significantly increased the odds of developing cancer (odds ratios (95% CI) 1.61 (1.17-2.20) and 1.03 (1.00-1.06), respectively) after adjusting for age, gender, and duration of immunosuppression. Class-switched memory B cells (CD19+CD27+IgD-) had a significant association to cancer, 1.04 (1.00-1.07). Receiver operator characteristic (ROC) curves for squamous cell carcinoma development within 100 days of immune phenotyping were significant for Tregs, memory B cells, and γδ T cells (AUC of 0.78, 0.68, and 0.65, respectively). After cancer resection, Treg, NK cell, and γδ T-cell numbers fell significantly. Immune-phenotype profiles associated with both squamous cell carcinoma and solid-organ cancer in kidney transplant recipients and depended on the presence of cancer tissue. Thus, immune profiling could be used to stratify kidney transplant recipients at risk of developing cancers to identify those who could qualify for prevention therapy.

Immune Checkpoint Inhibitors in Recipients of Renal Allografts.

Kidney transplant recipients are at increased risk of malignancy as a result of immunosuppression and are increasingly exposed to checkpoint inhibitors (CPIs). However, CPI therapy can precipitate allograft rejection. This review aims to summarize the current literature describing the epidemiology, immunological mechanisms, diagnosis, and treatment of CPI-associated allograft rejection.Initial studies of CPIs suggested allograft rejection post commencement of CPIs occured commonly (40-60%), occurring between 2 and 6 weeks after CPI initiation, with a cancer response rate approaching 50%. More recent studies with predefined, structured immunosuppressive regimens have seen rejection rates of 0-12.5%, with rejection occurring later. Allograft biopsy remains the mainstay of diagnosis; however, noninvasive tools are emerging, including donor-derived cell-free DNA, urinary chemokine assessment, and defining alloreactive T-cell clones prior to or during CPI therapy.

Quality of life of young adults and adolescents with chronic kidney disease.

OBJECTIVE: To elicit utility-based quality of life (QOL) in adolescents and young adults with chronic kidney disease (CKD). STUDY DESIGN: A cross-sectional study was conducted among patients aged 12-25 years with CKD stage 3-5 and 5D from 6 centers in Australia. QOL was measured using a visual analogue scale, and 3 utility-based QOL measures: Health Utilities Index Mark 2 and 3 (HUI2/3), Kidney Disease Quality of Life, incorporating the short form (SF)-12 transformed to SF-6D, and time trade-off (TTO). Multiple linear regression was used to define predictors for TTO QOL weights, SF-6D, and visual analogue scale scores. RESULTS: On a utility scale, with extremes of 0 (death) to 1 (full health), the 27 participants had a mean TTO QOL weight of 0.59 (SD = 0.40), HUI2 of 0.73 (SD = 0.28), HUI3 of 0.74 (SD = 0.26), and SF-6D of 0.70 (SD = 0.14). QOL weights were consistently low across the 4 utility-based instruments with widest variability in TTO responses. Mean QOL weights were higher among predialysis participants. The HUI2 indicated variability in the domain of emotion. From the Kidney Disease Quality of Life measures, decrements were observed in all QOL domains though dialysis patients reported a significantly higher burden attributed to kidney disease. CONCLUSIONS: Adolescent and young adults with CKD report low QOL values. Their utility-based QOL scores imply they are willing to trade considerable life expectancy for perfect health. Holistic care to improve QOL and minimize disease burden are imperative for optimizing health outcomes in young people with CKD, particularly those on dialysis.

Experiences and perspectives of adolescents and young adults with advanced CKD.

BACKGROUND: Young people with advanced chronic kidney disease experience delayed growth and poor psychosocial outcomes. This study aims to elicit the experiences and perspectives of young people waiting for a kidney transplant. METHODS: We conducted semistructured interviews with people aged 12-24 years from 6 Australian renal units. Participants also were asked to complete a journal. Interview transcripts and journal entries were analyzed thematically. RESULTS: 27 individuals participated in the study. 5 major themes were identified: inferiority (impaired body image, failing expectations, sick identity, and being a burden), insecurity (contending with prognostic uncertainty, vulnerability, and doubtful future), injustice (deprived of freedom, victimhood, and lost opportunity), resilience (autonomy and empowerment and maturity), and adjustment mentality (self-blame, reserved optimism, focusing on normality, and self-efficacy). CONCLUSIONS: Young dialysis- and non-dialysis-dependent patients with chronic kidney disease have an impaired sense of self-worth, perceive a precarious future, and feel limited in their physical and psychosocial capacities to have the same potential and opportunity as their healthy peers. Strategies to increase patient autonomy and self-efficacy in treatment management and to manage the emotional burdens of future uncertainties and lifestyle disruptions are needed to protect and promote the health and well-being of young people waiting for a kidney transplant.

Conversion to sirolimus in kidney transplant recipients with squamous cell cancer and changes in immune phenotype.

BACKGROUND: Conversion to sirolimus from calcineurin inhibitor- (CNI), azathioprine- (AZA) and mycophenolate-based regimens reduces the risk of development of squamous cell carcinoma of the skin (SCC) in kidney transplant recipients (KTRs). Sirolimus conversion may also be protective by permitting beneficial changes in immune phenotype. It is not known how sirolimus will affect immune phenotype in KTRs with SCC. METHODS: Thirty-two KTRs with SCC were enrolled into this single-blinded randomized study and 13 KTRs randomized to sirolimus (4-10 ng/mL) and prednisolone 5 mg/day. RESULTS: Six-month post conversion to sirolimus FOXP3(+) CD127(low)CD25(high)CD69(-), the number of T cells (putative Treg) increased significantly (P = 0.008). Natural killer (NK) and CD56(bright) NK cells also increased significantly (P = 0.039 and 0.02). T-cell number only significantly increased in those KTRs where CNI was ceased as part of the conversion to mammalian target of rapamycin inhibitors (mTORi's) (P = 0.031) implying CNI cessation rather than mTORi initiation induced an increase in T-cell number. Increases in the NK cell number was only significant in those KTRs where AZA was ceased (P = 0.040), implying AZA cessation rather than mTORi initiation caused the NK cell number to increase. At 6 months, sirolimus conversion reduces new SCC/year, rate ratio 0.49 (95%CI: 0.15-1.63), P = 0.276. On therapy analysis and intention-to-treat analysis over 24 months, the rate ratios were 0.84 and 0.87, respectively, and did not reach significance. CONCLUSIONS: Conversion to mTORi from CNI may reveal a pre-existing high Treg phenotype by unmasking CNI inhibition of FOXP3 expression. Cessation of AZA leads to increased NK cell number. High FOXP3(+) T-cell number on conversion to mTORi may predict those KTRs who continue to accrue SCC.

Human leukocyte antigen association with azathioprine-induced drug hypersensitivity reactions in patients with anti-neutrophil cytoplasmic antibody associated vasculitis.

Azathioprine (AZA) drug hypersensitivity reaction (DHR) is an uncommon yet potentially lethal condition that often goes unrecognised in patients with anti-Neutrophil Cytoplasmic Antibody (ANCA) associated vasculitis (AAV). We conducted a retrospective review of AAV patients on AZA maintenance therapy (N = 35). Participants were categorised into those who had experienced AZA-DHR (N = 15) and those who were AZA-tolerant (N = 20). Human leukocyte antigen (HLA) typing was performed in both groups. The primary endpoint was identification of a HLA gene association with AZA-DHR in the context of AAV. HLA-C*06:02, was solely expressed in AZA-DHR patients (33.3 %), whilst no patient who tolerated AZA carried this allele (0.0 %). This yielded a positive predictive value of 100 % for HLA-C*06:02 in predicting AZA-DHR in AAV patients, negative predictive value of 66.7 %, sensitivity of 33.3 % and specificity of 100 %. HLA-C*06:02 may predict the development of AZA-DHR in patients with AAV and inform safer therapeutic choice.

Immune phenotype predicts risk for posttransplantation squamous cell carcinoma.

Cutaneous squamous cell cancer (SCC) affects up to 30% of kidney transplant recipients (KTRs) within 10 years of transplantation. There are no reliable clinical tests that predict those who will develop multiple skin cancers. High numbers of regulatory T cells associate with poor prognosis for patients with cancer in the general population, suggesting their potential as a predictive marker of cutaneous SCC in KTRs. We matched KTRs with (n = 65) and without (n = 51) cutaneous SCC for gender, age, and duration of immunosuppression and assessed several risk factors for incident SCC during a median follow-up of 340 days. Greater than 35 peripheral FOXP3(+)CD4(+)CD127(low) regulatory T cells/microl, <100 natural killer cells/microl, and previous SCC each significantly associated with increased risk for new cutaneous SCC development (hazard ratio [HR] 2.48 [95% confidence interval (CI) 1.04 to 5.98], HR 5.6 [95% CI 1.31 to 24], and HR 1.33 [95% CI 1.15 to 1.53], respectively). In addition, the ratio of CD8/FOXP3 expression was significantly lower in cutaneous SCC excised from KTRs (n = 25) compared with matched SCC from non-KTRs (n = 25) and associated with development of new cutaneous SCCs. In summary, monitoring components of the immune system can predict development of cutaneous SCC among KTRs.

Long-Term Impact of Arteriovenous Fistula Ligation on Cardiac Structure and Function in Kidney Transplant Recipients: A 5-Year Follow-Up Observational Cohort Study.

Background: The long-term effects of arteriovenous fistula (AVF) ligation on cardiovascular structure following kidney transplantation remain uncertain. A prospective randomized, controlled trial (RCT) examined the effect of AVF ligation at 6 months on cardiovascular magnetic resonance imaging (CMR)-derived parameters in 27 kidney transplant recipients compared with 27 controls. A mean decrease in left ventricular mass (LVM) of 22.1 g (95% CI, 15.0 to 29.1) was observed compared with an increase of 1.2 g (95% CI, -4.8 to 7.2) in the control group (P<0.001). We conducted a long-term follow-up observational cohort study in the treated cohort to determine the evolution of CMR-derived parameters compared with those documented at 6 months post-AVF ligation. Methods: We performed CMR at long-term follow-up in the AVF ligation observational cohort from our original RCT published in 2019. Results were compared with CMR at 6 months postintervention. The coprimary end point was the change in CMR-derived LVM and LVM index at long-term follow-up from imaging at 6 months postindex procedure. Results: At a median of 5.1 years (interquartile range, 4.7-5.5 years), 17 patients in the AVF ligation group were studied with repeat CMR with a median duration to follow-up imaging of 5.1 years (IQR, 4.7-5.5 years). Statistically significant further reductions in LVM (-17.6±23.0 g, P=0.006) and LVM index (-10.0±13.0 g/m2, P=0.006) were documented. Conclusions: The benefit of AVF ligation on LVM and LVM index regression appears to persist long term. This has the potential to lead to a significant reduction in cardiovascular mortality.